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European Journal of Drug Metabolism and Pharmacokinetics

Michał Romański, Anna Zacharzewska, Artur Teżyk, Franciszek K Główka
BACKGROUND AND OBJECTIVES: Treosulfan is a prodrug applied in the treatment of ovarian cancer and conditioning prior to stem cell transplantation. So far, the bioanalysis of treosulfan in either whole blood or red blood cells (RBC) has not been carried out. In this work, the RBC/plasma partition coefficient (Ke/p ) of treosulfan and its active monoepoxide was determined for the first time. METHODS: Male and female 10-week-old Wistar rats (n = 6/6) received an intraperitoneal injection of treosulfan at the dose of 500 mg/kg body weight...
March 14, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Jing Zhan, Ya Ding, Benyan Zou, Hai Liao, Wenqi Jiang, Su Li
BACKGROUND AND OBJECTIVE: Puquitinib mesylate (XC-302) is a new multiple-target anticancer inhibitor, which directly suppresses the activity of phosphatidylinositol 3-kinase (PI3K). This study was aimed to develop a sensitive and specific liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS) method for the quantification and pharmacokinetic investigation of plasma puquitinib in cancer patients. METHODS: The analytes of human plasma were prepared by liquid-liquid extraction using methyl-t-butyl ether (MTBE)...
March 8, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Joshua I Hardt, Joel S Perlmutter, Christopher J Smith, Kevin L Quick, Ling Wei, Subhasish K Chakraborty, Laura L Dugan
BACKGROUND AND OBJECTIVES: Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C3 ), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys...
March 8, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Doreen Luedtke, Kristell Marzin, Arvid Jungnik, Ute von Wangenheim, Claudia Dallinger
BACKGROUND: Nintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib. METHODS: In the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences...
March 2, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Nuggehally R Srinivas
Pimasertib belongs to the growing family of mitogen activated protein kinase (MEK1/2) inhibitors undergoing clinical development for various cancer indications. Since the MEK inhibition in several cell signalling transduction cascades within tumours was considered therapeutically beneficial, number of clinical investigations of pimasertib have been reported. Despite being orally bioavailable in cancer patients, pimasertib undergoes faster clearance with a short elimination half-life. In addition, due to occurrence of toxicity, the development of pimasertib appears to be stalled...
February 27, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Ponnayyan Sulochana Suresh, Ravi Kumar Jairam, Devaraj V Chandrasekhar, Anera Balakrishna Vinod, Rakesh A Hiremath, Anusha Raj, Mohd Zainuddin, Ravi Kanth Bhamidipati, Ramesh Mullangi
BACKGROUND AND OBJECTIVES: Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. The primary objectives of the study were to evaluate the pharmacokinetics of ulixertinib in mice, rats, and dogs followed by prediction of human pharmacokinetic profile by allometric equations with/without correction factors. METHODS: Oral and intravenous pharmacokinetic profiles of ulixertinib were generated in mice, rats, and dogs. The human intravenous pharmacokinetics profiles [volume of distribution (Vss ) and clearance (CL)] were predicted employing simple allometry and using correction factors [maximum life span potential (MLP) and brain weight (BW)]...
February 22, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Qingshan Zhang, Gaowa Wang, Xi Chen, Zhiqiang Han, Xiangmei Chen, Risu Na, Haburi Jin, Ping Li, Renbatu Bu
BACKGROUND AND OBJECTIVES: Rhizoma coptidis extract and its alkaloids were reported to exhibit various pharmacological activities. However, pharmacokinetics investigations indicated that the plasma concentrations of the alkaloids were too low to explain their systemic therapeutic actions. Thus, the metabolic profile of Rhizoma coptidis in humans is yet to be fully investigated and the present study aimed to investigate the metabolic profile of Rhizoma coptidis in human urine after oral administration of Rhizoma coptidis extract...
February 15, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Ying Chen, Yang Deng, Miao Yan, Zhenyan Hou, Yao Li, Bikui Zhang, Hualin Cai
BACKGROUND AND OBJECTIVES: Risperidone is a derivative of benzisoxazole and is widely used for schizophrenia and other psychiatric illnesses in both adults and children. Previous studies have confirmed that it is a highly variable drug (within-subject variability ≥ 30%). To reduce the large sample size required for bioequivalence researches on highly variable drugs, a role for genotyping in the design of the bioequivalence study was employed. METHODS: A randomized, open-label, two-period crossover study was adopted: 20 subjects with specific genotypes carrying cytochrome P450 (CYP) 2D6*10 were randomized to two groups to receive a single oral dose of trial formulation or reference formulation with a 2-week washout period...
February 5, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Ashley Jahn, Charlie Bodreau, Kate Farthing, Fawzy Elbarbry
BACKGROUND AND OBJECTIVES: While some case reports indicate that high doses of propylene glycol (PG) may result in metabolic acidosis, there has been no large-scale study that evaluated the risk of metabolic acidosis in patients receiving PG-containing benzodiazepines for acute alcohol withdrawal. This study was undertaken to evaluate the potential toxicity of PG in patients with acute alcohol withdrawal treated with intermittent intravenous bolus doses of diazepam and/or lorazepam. METHODS: This is a retrospective case study using data collected from 18 randomly selected patients receiving one or both of these medications per a modified Clinical Institute Withdrawal Assessment for Alcohol (CIWA) Class 3 protocol...
February 1, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Ethan Miller, Munaf H Zalzala, Maryam S Abunnaja, Katsuhisa Kurogi, Yoichi Sakakibara, Masahito Suiko, Ming-Cheh Liu
BACKGROUND AND OBJECTIVES: Previous studies have demonstrated the metabolism of tibolone through sulfation, with the cytosolic sulfotransferase (SULT) SULT2A1 as the major responsible enzyme. The current study aimed to investigate how SULT2A1 genetic polymorphisms may affect the dehydroepiandrosterone (DHEA)- and tibolone-sulfating activity of SULT2A1. METHODS: Site-directed mutagenesis was employed to generate cDNAs encoding ten different SULT2A1 allozymes. Recombinant SULT2A1 allozymes were expressed in BL21 E...
February 1, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Meng Wang, Mengmeng Wang, Quanying Zhang, Shunlin Zong, Chengzhe Lv
BACKGROUND AND OBJECTIVES: Levetiracetam is a second-generation antiepileptic drug and distributed ubiquitously in the central nervous system. The extended-release formulation of levetiracetam was developed to provide patients with the convenience of once-daily dosing, to improve drug compliance and tolerability. The objective of this study was to evaluate the pharmacokinetics and safety of levetiracetam extended-release (ER) tablets in healthy Chinese subjects following single and multiple doses...
January 30, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Willi Cawello, Marina Braun, Jens-Otto Andreas
BACKGROUND AND OBJECTIVE: Pharmacokinetic studies using deconvolution methods and non-compartmental analysis to model clinical absorption of drugs are not well represented in the literature. The purpose of this research was (1) to define the system of equations for description of rotigotine (a dopamine receptor agonist delivered via a transdermal patch) absorption based on a pharmacokinetic model and (2) to describe the kinetics of rotigotine disposition after single and multiple dosing...
January 13, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Aravind Mittur
BACKGROUND AND OBJECTIVE: Nefopam is a non-opioid, non-steroidal, central analgesic thought to act via multiple mechanisms including potent inhibition of serotonin-norepinephrine reuptake and modulation of voltage-sensitive calcium and sodium channels. There has been a resurgence in its use for postoperative pain and neuropathic pain. Dosing route-dependent metabolism and clinical effects have been described following intravenous and oral nefopam. N-desmethylnefopam and nefopam N-oxide are metabolites of clinical interest...
January 5, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Margaux Boehler, Shirin Bruderer, Ivan Ulč, Jasper Dingemanse
BACKGROUND AND OBJECTIVES: Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg selexipag (Treatment A) vs. 4 paediatric tablets of 50 µg (Treatment B) in healthy adult male subjects...
February 2018: European Journal of Drug Metabolism and Pharmacokinetics
Janthima Methaneethorn
BACKGROUND AND OBJECTIVES: Even though lithium has been used for the treatment of bipolar disorder for several decades, its toxicities are still being reported. The major limitation in the use of lithium is its narrow therapeutic window. Several methods have been proposed to predict lithium doses essential to attain therapeutic levels. One of the methods used to guide lithium therapy is population pharmacokinetic approach which accounts for inter- and intra-individual variability in predicting lithium doses...
February 2018: European Journal of Drug Metabolism and Pharmacokinetics
Francis S Wolenski, Cindy Q Xia, Bingli Ma, Tae H Han, Wen C Shyu, Suresh K Balani
BACKGROUND AND OBJECTIVES: Monomethyl auristatin E (MMAE), the toxin linked to CD30-specific monoclonal antibody of Adcetris® (brentuximab vedotin), is a potent anti-microtubule agent. Brentuximab vedotin has been approved for the treatment of relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Cytochrome P450 (CYP) induction assessment of MMAE was conducted in human hepatocytes to assess DDI potentials and its translation to clinic. METHODS: MMAE was incubated at 1-1000 nM with cultured primary human hepatocytes for 72 h, and CYP1A2, CYP2B6, and CYP3A4 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction and CYP-specific probe substrate by liquid chromatography coupled with mass spectrometry, along with microtubule disruption by immunofluorescence staining using anti-β-tubulin antibody and imaging...
December 20, 2017: European Journal of Drug Metabolism and Pharmacokinetics
Fawzy Elbarbry
After more than six decades of its use as the mainstay antibiotic for the treatment of multidrug-resistant Gram-positive bacterial infections, dosing and monitoring of vancomycin therapy have not been optimized. The current vancomycin therapeutic guidelines recommend empiric doses of 15-20 mg/kg administered by intermittent infusion every 8-12 h in patients with normal kidney function. Additionally, the guidelines recommend trough concentration of 15-20 mg/L as a therapeutic goal for adult patients with severe infections...
December 19, 2017: European Journal of Drug Metabolism and Pharmacokinetics
Prashant B Nigade, Jayasagar Gundu, K Sreedhara Pai, Kumar V S Nemmani
BACKGROUND: Predicting target site drug concentrations is of key importance for rank ordering compounds before proceeding to chronic pharmacodynamic models. We propose generic tumor-specific correlation-based regression equations to predict tumor-to-plasma ratios (tumor-Kps) in slow- and fast-growing xenograft mouse models. METHODS: Disposition of 14 basic small molecules was investigated extensively in mouse plasma, tissues and tumors after a single oral dose administration...
December 18, 2017: European Journal of Drug Metabolism and Pharmacokinetics
William L Marshall, Hwa-Ping Feng, Larissa Wenning, Graigory Garrett, Xiaobi Huang, Fang Liu, Deborah Panebianco, Luzelena Caro, Christine Fandozzi, Kenneth C Lasseter, Richard A Preston, Thomas Marbury, Joan R Butterton, Marian Iwamoto, Wendy W Yeh
BACKGROUND: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. OBJECTIVE: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. METHODS: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study...
December 15, 2017: European Journal of Drug Metabolism and Pharmacokinetics
Maaike A Sikma, Claudine C Hunault, Johannes H Kirkels, Marianne C Verhaar, Jozef Kesecioglu, Dylan W de Lange
BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is frequently observed after heart transplantation and is associated with morbidity and mortality. However, many confounding factors also contribute to the development of AKI in heart transplants. We hypothesized that supratherapeutic whole-blood tacrolimus trough concentrations are associated with AKI. METHODS: In a retrospective observational cohort from April 2005 to December 2012, all adult heart transplantation patients were included...
December 13, 2017: European Journal of Drug Metabolism and Pharmacokinetics
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